Regulation of ABO blood group antigen expression by miR-331-3p and miR-1908-5p during hematopoietic stem cell differentiation

Abstract

The ABO blood group system is the most important factor in clinical transfusion medicine and is implicated in a number of human diseases. ABO antigens are not confined to red blood cells (RBCs) and are widely expressed in a variety of human cells and tissues. To date, many alleles with variant ABO expression have been identified and in many cases traced to one of the >250 reported genetic variations in the respective glycosyltransferase. The role of microRNAs (miRNAs) in the regulation of blood group antigens during erythropoiesis has not been addressed, however. Here, we show that miR-331-3p and miR-1908-5p directly target the mRNA of glycosyltransferases A and B. Expression levels of miR-331-3p and miR-1908-5p inversely correlated with levels of blood group A antigen. In addition, we found that overexpression of these miRNAs in hematopoietic stem cells led to a significantly reduced number of blood group A antigens per RBC. Simultaneous targeting of the transcription factor (TF) SP1 by miR-331-3p further enhanced these effects. The targeting rendered SP1 incapable of binding to the ABO gene promoter, causing further downregulation of blood group A antigen expression by up to 70%. Taken together, expression changes in these miRNAs may account for rare cases of weak A/B phenotypes that genetic variations in the glycosyltransferase coding region cannot explain. These results also suggest an explanation for the disappearance of ABH antigens during carcinogenesis and point to new therapeutic targets in ABO mismatched organ transplantation.

Integrated Analysis of Hub Genes and MicroRNAs in Human Placental Tissues from In Vitro Fertilization-Embryo Transfer

“…SP1 has been shown to regulate the placental glucocorticoid barrier by repressing the expression of 11β-hydroxysteroid dehydrogenase type 2, leading to fetal growth restriction (FGR) ( 38 ). One study identified the interaction of miR-331-3p with SP1 and the interaction of miR-331-3p and miR-1908-5p with glycosyltransferases as a novel mechanism for ABO blood group regulation ( 39 ). The second ranked hit in the TF analysis was EGR1 which has been previously implicated in follicular development, ovulation, corpus luteum formation and placental angiogenesis ( 40 ), and plays a key role in placental implantation ( 41 ).…”

Six splice site variations, three of them novel, in the ABO gene occurring in nine individuals with ABO subtypes

“…These variants of the ABO gene are located in the CDS region, intron 1 erythroid-specific regulatory element region, splice site, promoter, cis- or trans-regulatory element, etc. Kronstein-Wiedemann R et al found that miR-331-3p and miR-1908-5p directly target the mRNA of GTA and GTB and that overexpression of these miRNAs in haematopoietic stem cells may result in a significant reduction in the expression of A antigens [ 30 ]. Some variations in the splice sites of the ABO gene are associated with some ABO subtypes.…”

ABO Blood Group and the Risk and Prognosis of Lymphoma

“…The underlying mechanisms that the ABO blood group may interact with the development and progression of cancers including lymphoma are still poorly understood. Several plausible potential pathogenic ways encompass: 1) Deletion of ABO blood group antigens caused by multiple regulators enhances the motility and migration of tumor cells, resulting in poor prognosis; 15,[22][23][24][25][26][27] 2) Tumor markers that are ABO blood group antigens can evade the immune surveillance of host and allow tumors to grow; [13][14][15][16] 3) Dysregulation of ABO glycosyltransferases, which are mainly involved in altering the modulator of angiogenesis during the tumorigenesis, is related to tumor; [28][29][30][31] and 4) The influence of ABO blood group antigens on tumor growth, invasion and migration is mainly related to the ABO gene locus involved in regulating the mediators of inflammation and immune responses (Figure 1). 18,[32][33][34][35][36] The decrease or absence of ABO blood group antigen expression seems to play a role in the progression of tumors.…”

“…First, the deletion of ABO allele or hypermethylation of the ABO promoter region causes relative down-regulation of the glycosyltransferase necessary for blood group antigen synthesis. 22,[37][38][39][40] Second, some microRNAs (miRNAs) affect the expression of blood group antigens by regulating the activity of glycosyltransferase, such as miR-331-3p and miR-1980-5-p. 27 Third, mutations in the ABO gene. For example, the mutation of the GATA motif in intron 1 of the ABO gene could reduce the expression of the B antigen, and mutation of RUNX1 causes the loss of A antigen.…”